Human Polymorphonuclear Leukocytes Generate and Degrade Endothelin-1 by Two Distinct Neutral Proteases

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Abstract
Summary: Human polymorphonuclear leukocytes (PMNs, 4 x 106/ml) converted human big endothelin (bET) to an endothelin-1 (ET-l)-like contractile factor, as assessed by bioassay. The formation of this ET-1-like activity from bET was partially inhibited by phosphoramidon (54 μ/ml), but not by pepstatin-A (1μ/ml), epoxysuccinyl-L-leucylamido(guanidino)butane (E-64, 10 μ/ml) or phenylmethylsulfonyl fluoride (PMSF, 25 μ/ ml). In addition, nonactivated PMNs converted I125I]bET to [125I]ET-1, thus confirming the bioassay results. Incubation of ET-1 with fMLP-activated PMNs or cell-free supernatants from activated PMNs resulted in the loss of its contractile activity, and this loss of activity was paralleled by the metabolism of [125I]ET-l. The metabolism of [I2SI]ET-1 by PMNs or leukocyte cathepsin G (5 μ/ ml) was prevented by PMSF (25 μ/ml), but not by phos-phoramidon (54 μ/ml) or pepstatin-A (1 μ/ml). Thus, PMNs can form ET-1 from bET via a neutral protease and degrade ET-1 via a serine protease, an observation that may have important pathophysiologic implications in disease states associated with PMN infiltration.

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